Red Flags for early referral of people with symptoms suggestive of narcolepsy: a report from a national multidisciplinary panel.

OBJECTIVE: Narcolepsy is a lifelong disease, manifesting with excessive daytime sleepiness and cataplexy, arising between childhood and young adulthood. The diagnosis is typically made after a long delay that burdens the disease severity. The aim of the project, promoted by the "Associazione Italiana Narcolettici e Ipersonni" is to develop Red Flags to detect symptoms for early referral, targeting non-sleep medicine specialists, general practitioners, and pediatricians. MATERIALS AND METHODS: A multidisciplinary panel, including patients, public institutions, and representatives of national scientific societies of specialties possibly involved in the diagnostic process of suspected narcolepsy, was convened. The project was accomplished in three phases. Phase 1: Sleep experts shaped clinical pictures of narcolepsy in pediatric and adult patients. On the basis of these pictures, Red Flags were drafted. Phase 2: Representatives of the scientific societies and patients filled in a form to identify barriers to the diagnosis of narcolepsy. Phase 3: The panel produced suggestions for the implementation of Red Flags. RESULTS: Red Flags were produced representing three clinical pictures of narcolepsy in pediatric patients ((1) usual sleep symptoms, (2) unusual sleep symptoms, (3) endocrinological signs) and two in adult patients ((1) usual sleep symptoms, (2) unusual sleep symptoms). Inadequate knowledge of symptoms at onset by medical doctors turned out to be the main reported barrier to diagnosis. CONCLUSIONS: This report will hopefully enhance knowledge and awareness of narcolepsy among non-specialists in sleep medicine in order to reduce the diagnostic delay that burdens patients in Italy. Similar initiatives could be promoted across Europe.

Predictive value of the number of adverse reaction episodes for the IgE-mediated food allergy diagnosis.

INTRODUCTION AND OBJECTIVES: The reproducibility of the adverse reaction increases the suggestiveness of a history of food allergy. However, the positive predictive value (PPV) of multiple adverse reaction episodes for the diagnosis of IgE-mediated food allergy is not known. This evaluation was the objective of our study. PATIENTS AND METHODS: We retrospectively studied 180 children with a history of non-anaphylactic adverse reactions after the ingestion of a food. All children had the prick test positive for the offending food and performed the oral food challenge (OFC) within 12 months after the last adverse reaction episode (ARE). We have evaluated whether increasing the number of ARE increased the probability that the OFC would be positive (failed). RESULTS: 93 patients (52%) presented one ARE, 49 (27%) presented two ARE, 24 (13%) presented three ARE, 14 (8%) patients presented≥four ARE. The OFC was positive in 94/180 (52%). The outcome of the OFC was found to be positively correlated with the number of ARE (OR=1.56; 95% CI=1.16-2.09; p=0.003). A PPV=100% was observed with a number of ARE≥five. CONCLUSIONS: The number of ARE is an important predictor of the diagnosis of food allergy, although less than we would have imagined. The number of ARE could be used to increase the predictability of the diagnostic tests currently in use, to define clinical prediction rules alternative to OFC and easy to use in clinical practice.

Yogurt is tolerated by the majority of children with IgE-mediated cow's milk allergy.

BACKGROUND: Children with IgE-mediated cow's milk allergy (IgE-CMA) with gastrointestinal symptoms tolerate yogurt at 100%. Yogurt tolerance in children with IgE-CMA with urticaria and anaphylaxis was 7%. METHODS: We enrolled children with IgE-CMA with cutaneous, respiratory, gastrointestinal and anaphylactic symptoms. All performed prick by prick (PbP) and oral food challenge (OFC) with yogurt. Some children performed also an OFC with CM mixed with wheat flour and baked, baked liquid CM, parmesan. RESULTS: 34 children were enrolled, 31/34 (91%) with systemic adverse reaction after ingestion of CM (systemic CMA), 3/34 (9%) with isolated contact urticaria (ICU CMA). PbP with yogurt was negative only in one patient. OFC with yogurt was passed (that is, the OFC was negative) by 20/31 (64%) of the children with systemic CMA. 10/11 (91%) of the patients who failed OFC (that is, the OFC was positive) with yogurt were positive to SPT with casein vs. 8/20 (40%) of the patients who passed it (p=0.018). None of the 19 children who passed OFC with yogurt failed all OFC with processed CM forms other than yogurt that tested vs. 4/8 among those who failed OFC with yogurt (p=0.006). The rub test with yogurt was negative in 1/3 (33%) of the patients with ICU CMA. CONCLUSIONS: The results of our study are placed alongside others already present in the literature and concerning other methods of processing CM proteins and help to reduce the dietary restrictions of the majority of children with systemic IgE-CMA.

Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: Grass pollen-related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

Prevalence, molecular characterization, and clinical relevance of sensitization to Anisakis simplex in children with sensitization and/or allergy to Dermatophagoides pteronyssinus.

SUMMARY: Prevalence of the Anisakis Simplex's (AS) sensitization in children sensitized to Dermatophagoides pteronissynus (DP) is not known, neither it is to which percentage it might be due to cross-reactivity. The primary objective of the present retrospective cross-sectional study is to evaluate the prevalence of sensitization to AS in children sensitized or allergic to DP. Secondary outcomes were the prevalence of cross-reactivity and clinical relevance of the condition. The prevalence of sensitization to AS differs significantly among patients sensitized and not to DP (13.43% vs. 3.80%; p=0.019). The higher prevalence is mainly due to cross-reactivity with Der p10 (OR=8.86; 95% CI=4.33-40.74; p=0.0001). Currently, the sensitization to AS seems to have no clinical relevance in the pediatric population.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

The oral food desensitization in the Italian allergy centres.

BACKGROUND: Attempts aimed at inducing food tolerance through oral food desensitization (OFD) for the treatment of IgE-mediated food allergies are increasing. In Italy, a number of allergy centres offer this procedure. OBJECTIVE: To collect information on how these centres are organized, how patients are selected, the methods used to administer OFD and how adverse reactions are managed. METHODS: A questionnaire was e-mailed to all the Italian allergy centres offering OFD. RESULTS: The survey shows a high degree of variability between centres. A correct diagnosis of food allergy is crucial for selecting patients for OFD. In the Italian allergy centres, oral food challenges are mostly open label (84%), but in 16% of cases they are single-blind (8%) or double-blind (8%). A high proportion of allergy centres (83%) offer OFD to children presenting forms of anaphylaxis triggered by traces--or very low doses--of food allergen. The majority of allergy centres (76%) enroll patients over 3 years of age, with 44% enrolling patients above the age of 5. Not-controlled asthma, unreliability of parents in the management of OFD and/or risk of adverse events, are the main reasons for exclusion from the procedure. CONCLUSION: Although OFD may sometimes be successful and may be considered a valid alternative to an elimination diet, further randomized controlled trials are needed, in order to clarify some controversial points, such as the characteristics of the child undergoing OFD, and the methods of food preparation and administration. Moreover, further studies should further investigate OFD safety, efficacy and costs.

Sudden loss of cow's milk tolerance in a long-sensitized patient.

The prevalence of food allergy and anaphylaxis in children is reported to be increasing in recent years. Evidence suggests that exposure to large doses of antigen favors the maintenance of tolerance. We report a case of sudden loss of cow's milk tolerance in a long-sensitized girl with celiac disease after a short period of milkless diet. We hypothesize that the continuous intake of high quantities of antigen sustained tolerance despite high levels of specific IgE and that, in the presence of epithelial barrier dysfunction caused by celiac disease, the few weeks of allergen-free diet led to a rapid loss of tolerance.

Effects of deconjugated bile acids on electrolyte and nutrient transport in the rabbit small intestine in vitro.

To obtain new information on the poorly investigated mechanisms of the diarrheogenic effects of bile acids, we investigated the effects of the unconjugated bile acids chenodeoxycholate and ursodeoxycholate on the small intestine transport of electrolytes and nutrients in the rabbit jejunal and ileal mucosa mounted in vitro in Ussing or influx chambers. When added to the ileal mucosa at a concentration of 1 mM, both bile acids induced a secretory shift in ion transport; absorption of Na and Cl was abolished and secretion of bicarbonate was enhanced. No changes in short circuit current or electrolyte transport were observed when the bile acids were added to the jejunal mucosa. The addition of 1 mM chenodeoxycholate to the luminal side of the ileum induced a marked inhibition in the uptake of glucose, phenylalanine, and glutamic acid. A similar inhibition, though of a lesser magnitude, was also induced by both bile acids on jejunal nutrient transport. Further studies on the inhibitory effect of chenodeoxycholate on glucose influx showed that the inhibition was dose-dependent; at 1 mM it was maximal and resulted in the complete abolition of the active component, with only the diffusional pathway still operative. We conclude that unconjugated bile acids act as secretagogues in the ileum and significantly blunt the active transport of nutrients in the small intestine. Both effects may well play a role in the diarrheogenic action of these bile acids.

Pathogenesis of postantibiotic diarrhoea caused by Clostridium difficile: an in vitro study in the rabbit intestine.

To elucidate the pathophysiological changes leading to postantibiotic diarrhoea caused by Clostridium difficile and its cytotoxin, oral ampicillin was given to rabbits, and jejunal, ileal, and caecal segments of those that developed diarrhoea were investigated in vitro. The rabbits that, in response to treatment, harboured Clostridium difficile in their colonic lumen were studied, and the results expressed according to the presence or absence of Clostridium difficile and/or its cytotoxin. Thus, we refer to either CD+ or CD- segments. The influx of glucose, phenylalanine, glycylphenylalanine, and lysine across the brush border of jejunum and ileum of CD+ segments was severely impaired, while only slightly blunted in CD-. No significant change was detected in the influx of glutamic acid in the jejunum of all treated animals and in the CD- ilea. Morphologic damage in ileum and caecum of CD+ was also more evident than in CD-. Transepithelial ion transport across short circuited ileal mucosa (CD+ and CD-) revealed secretory changes in Cl net transport that were more marked in CD-. We conclude that: (1) Clostridium difficile may also colonise the upper intestinal tract, where it induces morphological and functional damage, severely impairing nutrient absorption; and (2) the ileum contributes to the diarrhoea caused by CD even when the micro-organism is confined to the more distal gut by showing moderate impairment of nutrient absorption and marked electrolyte secretion.